title: Deoxyhypusine synthase haploinsufficiency attenuates acute cytokine signaling.
abstract: Deoxyhypusine synthase (DHS) catalyzes the post-translational formation of the amino acid hypusine. Hypusine is unique to the eukaryotic translational initiation factor 5A (eIF5A), and is required for its functions in mRNA shuttling, translational elongation, and stress granule formation. In recent studies, we showed that DHS promotes cytokine and ER stress signaling in the islet β cell and thereby contributes to its dysfunction in the setting of diabetes mellitus. Here, we review the evidence supporting a role for DHS (and hypusinated eIF5A) in cellular stress responses, and provide new data on the phenotype of DHS knockout mice. We show that homozygous knockout mice are embryonic lethal, but heterozygous knockout mice appear normal with no evidence of growth or metabolic deficiencies. Mouse embryonic fibroblasts from heterozygous knockout mice attenuate acute cytokine signaling, as evidenced by reduced production of inducible nitric oxide synthase, but show no statistically significant defects in proliferation or cell cycle progression. Our data are discussed with respect to the utility of sub-maximal inhibition of DHS in the setting of inflammatory states, such as diabetes mellitus.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Templin
authors.forename: Bernhard
authors.initials: B
authors.lastname: Maier
authors.forename: Yurika
authors.initials: Y
authors.lastname: Nishiki
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Tersey
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology; D005347:Fibroblasts / Q000378:metabolism; D057895:Haploinsufficiency / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D010448:Peptide Initiation Factors / Q000378:metabolism*; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D016207:Cytokines; D052247:Nitric Oxide Synthase Type II; D000587:Oxidoreductases Acting on CH-NH Group Donors; D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C063507:deoxyhypusine synthase